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Back to 2018 Program and Abstracts THE GUT-LIVER AXIS: PROBING THE PORTAL SYSTEM AS THE SOURCE OF INFLAMMATION IN ACUTE AND CHRONIC DISEASES Fatemeh Adiliaghdam*1, Florian Kuehn1, Juan Ramírez Decrescenzo1, Sulaiman R. Hamarneh1, Laurence Rahme1,2, Richard Hodin1 1Department of surgery, Massachusetts General Hospital, Cambridge, MA; 2Shriners Hospitals For Children, Boston, MA Background: An impaired gut barrier is associated with a variety of diseases,including severe burns,alcohol-induced liver damage,and aging. The portal system sits at the interface between the host and the inflammatory mediators that exist within the gut.We therefore sought to explore portal system mediators present in the setting of gut barrier dysfunction in order to identify novel therapeutic targets.Methods: We assessed portal vein pro-inflammatory characteristics in a 30% back burn and ethanol-induced liver injury(binge ethanol dose,5 g/kg every12 hours for a total of 3doses by gastric gavage) as acute disease models.In addition,we used aging as a model of chronic,low-grade chronic inflammation.Given the role of the gut brush border enzyme intestinal alkaline phosphatase (IAP)as an anti-inflammatory enzyme and gut barrier regulator,the burned and alcohol-exposed mice were treated+/-oral IAP. Portal vein serum+/-PolymixinB(to deplete active LPS)was applied in vitro to primary mouse macrophages and inflammatory gene expression assessed using qPCR.Results:Burn model:Compared to sham controls,the portal serum from burned-mice contained more LPS(10.4 vs 4.2 EU/L,p<0.05) and had a much higher(3.3 fold, p<0.001)pro-inflammatory impact on the macrophages.The inflammatory impact of the portal serum was largely preserved even after Polymixin B incubation,suggesting the presence of non-LPS mediators.Oral IAP treatment 3hour post-burn)markedly decreased the levels of portal LPS(10.4 vs 6.5 EU/L,p<0.05) and blocked the pro-inflammatory effects on macrophages(p<0.01)and resulted in much lower cytokine levels in the liver and systemic blood(1.6-and1.7-fold changes,respectively).Alcohol-induced liver damage:Compared to vehicle-treated mice, portal serum from alcohol-gavaged mice showed more of an inflammatory impact on the macrophages(3.7-fold difference,p<0.01).As in the burn model,oral IAP treatment significantly blocked the increase in hepatic inflammation and portal LPS levels(1.6and 1.8-fold changes,respectively).Similarly,portal serum from the IAP-treated mice exerted much less inflammatory impact on target cells,(2.4-fold change,p<0.01).Aging model: Aging progressively caused gut barrier dysfunction which led to low-grade systemic and liver inflammation(p<0.05).The amount of LPS in portal serum increased as a function of age(1.4-fold p<0.001).Portal serum from aged mice contained more pro-inflammatory mediators(2.73 fold increase, p<0.05).This phenotype was even more dramatic in IAP KO mice.(3.44-fold increase,p<0.001).Conclusion:Portal vein serum contains pro-inflammatory mediators (LPS and others) in both acute and chronic models, indicating that this could a source to identify novel therapeutic targets. Prevention of a "leaky" gut with oral IAP may represent a novel therapy to prevent a variety of gut-induced systemic inflammatory conditions. Back to 2018 Program and Abstracts |
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